The present invention relates to a newly stabilized HMG-CoA reductase inhibitor which is used in a pharmaceutical formulation being particularly suitable for the treatment of hypercholesterolemia and hyperlipidemia.
More precisely, the present invention relates to a stabilized and very homogeneous composition mixture comprising a HMG-CoA reductase inhibitor, such as atorvastatin, pravastatin, fluvastatin and cerivastatin, or pharmaceutically active salts thereof, as well as solid pharmaceutical formulations containing the aforementioned homogeneous composition mixture as an active substance. The present invention relates more particularly to a stabilized and very homogeneous composition mixture comprising a HMG CoA reductase inhibitor or its pharmaceutically active salts, as well as solid pharmaceutical formulations containing the aforementioned homogeneous composition mixture as an active substance and which has increased stability as determined by a small change of its pH value and lactone content under storage and/or handling conditions. The present invention relates most particularly to a stabilized and very homogeneous composition mixture comprising pravastatin or its pharmaceutically active salts, as well as solid pharmaceutical formulations containing the aforementioned homogeneous composition mixture as an active substance and which has increased stability as determined by a small change of its pH value and lactone content under storage and/or handling conditions.
Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, fluvastatin and cerivastatin, derivatives and analogs thereof are known as HMG-CoA reductase inhibitors and are used as antihypercholesterolemic agents. The majority of them are produced by fermentation using microorganisms of different species identified as species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus. Some are obtained by treating the fermentation products using the methods of chemical synthesis like simvastatin or they are the products of total chemical synthesis like fluvastatin, atorvastatin and cerivastatin.
The purity of the active substance is an important factor for manufacturing a safe and effective pharmaceutical formulation. Maximum possible purity of the product is of particular importance if the pharmaceutical product must be taken on a longer term basis in the treatment or prevention of high cholesterol levels in blood. Accumulation of impurities from drugs of a lower level of purity may cause a variety of side effects during treatment. Besides impurities that cannot be completely eliminated in the process of preparation of the active substance degradation products occurring by subjecting the final pharmaceutical formulation to various environmental factors such as temperature, moisture, low pH, carbon dioxide from the air and light, may also impose a significant problem. HMG-CoA reductase inhibitors occurring in the form of salts in the final pharmaceutical formulation, such as atorvastatin, pravastatin, fluvastatin and cerivastatin, are particularly sensitive to an acidic environment in which hydroxy acids are degraded into a lactone.
Apart from the fact that the aforementioned active substance may be destabilized by the environmental factors, their degradation may also be accelerated by interactions with other pharmaceutical ingredients, such as fillers, binders, lubricants, glidants and disintegrating agents.
Therefore, the pharmaceutical ingredients and the process for preparation of the pharmaceutical formulation should be meticulously chosen to avoid the aforementioned undesired interactions and reactions.
The stability of the active substance in an acidic environment is one of the major problems in the case of statins in the form of salts. One of possible solutions of the aforementioned problem is described in EP 0 336 298, U.S. Pat. No. 5,030,447 and U.S. Pat. No. 5,180,589, disclosing a stable pharmaceutical formulation for pravastatin. The essence of the formulation is to maintain an alkaline environment so that the aqueous dispersion of the pharmaceutical formulation reaches a pH above 9, preferably about 10. In addition to the active substance pravastatin, the composition of the invention includes a basifying agent, such as magnesium oxide, which imparts a pH to an aqueous dispersion of the aforementioned formulation above 9. In view of the stability of the active substance such a formulation is effective. These references disclose the pharmaceutical composition in a tablet form being subjected to a stability study at 60xc2x0 C. or 40xc2x0 C. and 75% relative humidity for a period of up to 2 or several months, wherein no lactone formation was observed. However, the local alkaline environment occurring at the site of dissolution of the pharmaceutical formulation may have a negative impact on the gastric mucosa with its normally acidic environment, especially since a relatively high amount of basifying agent is necessary to ensure acceptable stability. This negative impact may be particularly evident for patients with a damaged gastric mucous membrane where the mucosa per se is not able to create a sufficient acidic environment inside the stomach for normal digestive functioning. It is particularly important in chronic therapies as in the case of prophylaxis or treatment with HMG-CoA reductase inhibitors.
Another approach for providing a stable pharmaceutical formulation is described in the present Applicant""s earlier PCT application No. PCT/IB99/01749 with publication No. WO 00/35425, which discloses stabilization of an HMG CoA reductase inhibitor in a solid formulation with a buffering agent. Among the HMG CoA reductase inhibitors disclosed are pravastatin, atorvastatin, fluvastatin and cerivastatin, which are said and known to be particularly sensitive to an acidic environment. The pH of the active substance is thus adjusted within the range from 7 to 11 in an aqueous medium in the course of preparing the salt of the HMG CoA reductase inhibitor from the acid form and an alkaline substance and additionally the active substance is further mixed with an appropriate buffering agent. The active substance contains small amounts of a buffering agent, preferably less than 1%, more preferably 0.1 to 0.5% and most preferably approximately 0.3% based on the weight of the active substance.
Among the buffering agents used for stabilizing the active substance are disclosed carbonate buffer or phosphate buffer, such as sodium carbonate. In addition to this the final pharmaceutical formulation of active substance and other excipients is further stabilized by a further addition of a buffering agent so as to provide a pH lower than 9 of a pharmaceutical formulation in an aqueous medium. This is achieved by addition of 20%, more preferably by 10% per weight based on the total weight of the tablet. Among the suitable buffering agents to stabilize such a pharmaceutical formulations are disclosed sodium and magnesium carbonate, sodium phosphate, sodium and potassium citrate, dibasic sodium phosphate, calcium carbonate, hydrogen phosphate, phosphate, sulfate, sodium ascorbinate, benzoate, sodium or potassium hydrogen carbonate, lauryl sulfate or mixtures thereof.
Stable pharmaceutical compositions containing 7-substituted-3,5-dihydroxyheptanoic acids or 7-substituted-3,5-dihydroxyheptenoic acids are disclosed in WO 0176566 and US 20020035142. Among 7-substituted-3,5-dihydroxyheptanoic acids are disclosed pravastatin and atorvastatin and their pharmaceutically acceptable acid salts. These compounds in such stable pharmaceutical compositions are stabilized by a stabilizing effective amount of at least one amido-group containing polymeric compound or at least one amino-group containing polymeric compound or a combination thereof, wherein said stabilized pharmaceutical composition does not contain a stabilizing effective amount of another stabilizer or a combination of other stabilizers. Disclosed is also a lactone content of such compositions in tablet form with other excipients upon subjecting the tablet compositions to a PVDC/PVC blister stability study at 40xc2x0 C./75% relative humidity for up to 3 or 6 months. Pravastatin sodium compositions disclosed have lactone content based on the weight percentage at time 0 of from 0.0% to 0.6% depending on the composition, excipients and active agent and after 1 month study of from 0.2% to 1.5% depending on the composition, excipients and active agent. Disclosed pravastatin sodium formulations have lactone content of 0.0% at time 0 and of from 0.2% to 1.5% after 1 month study depending on the composition and its excipients.
Crystalline forms of atorvastatin hemi calcium salt are disclosed in U.S. Pat. No. 5,969,156 and WO 9703959, which are produced from atorvastatin lactone by help of sodium hydroxide to form a ring-opened sodium salt of atorvastatin and by help of calcium acetate hemihydrate to convert the thus obtained sodium salt into a form of a calcium salt of atorvastatin. The two agents sodium hydroxide and calcium acetate hemihydrate are here used for production of crystalline atorvastatin.
Known and disclosed stabilized compositions of HMG CoA reductase inhibitors are compositions, which are mixtures of a respective HMG CoA reductase inhibitor and more than one pharmaceutical excipient or of a respective HMG CoA reductase inhibitor and a basifying agent selected from the group of inorganic alkaline and alkaline earth metal oxides and hydroxides.
An active substance of the pravastatin sodium with a certain lactone content, namely substantially pure pravastatin sodium or pravastatin sodium with lactone content of less than 0.5% or less than 0.2%, is disclosed in WO 0230415 and US 20020082295, wherein such pravastatin sodium is obtained by a specified process for recovering pravastatin sodium from a fermentation broth in high purity, comprising a specified sequence of steps. The specified steps are forming an enriched organic solution of pravastatin, precipitating pravastatin as ammonium salt, purifying the ammonium salt by recrystallization, transposing the ammonium salt to pravastatin sodium and isolating pravastatin substantially free of pravastatin lactone and epipravastatin. This document does not teach about stabilizing of this active substance or its composition.
There continues to be the need to prepare a stabilized active substance of HMG-CoA reductase inhibitor or its pharmaceutically active salts, which will provide pH values and lactone contents that will remain stable under normal storage and/or handling conditions along the time and the change of which will be small under stressed storage conditions along the time. Such an active substance is provided in accordance with the present invention.
It is an object of the present invention to provide a pharmaceutical formulation containing as an active substance a HMG-CoA reductase inhibitor which exerts an excellent stability while avoiding the aforementioned disadvantages.
It is a particular object to provide a stabilized active substance as such, i.e. before being formulated into the pharmaceutical formulation, where the HMG-CoA reductase inhibitor is precautionary protected from being degraded.
It is a further object to provide a process for the preparation of a stabilized HMG-CoA reductase inhibitor which exerts an excellent stability while avoiding the aforementioned disadvantages. It is also an object of this invention to prepare a stabilized active substance of HMG-CoA reductase inhibitor or its pharmaceutically active salts, which will provide pH values and lactone contents that will remain stable under normal storage and/or handling conditions along the time and the change of which will be small under stress storage conditions along the time.
These and further objects are accomplished by the present invention.
According to the present invention, there is provided a composition comprising a homogeneous mixture of a HMG-CoA reductase inhibitor with a buffering substance or a basifying substance, which composition has been obtained by co-crystallization and/or co-precipitation of said HMG-CoA reductase inhibitor and said buffering substance or basifying substance.
By means of co-crystallization and/or co-precipitation, the obtained dried HMG-CoA reductase inhibitor compound itself is mixed with the buffering substance or the basifying substance in a very homogeneous and finely distributed form. It is believed that the buffering substance or the basifying substance is finely distributed around the HMG-CoA reductase inhibitor crystals, thus forming a kind of protective xe2x80x9cmicroenvironmentxe2x80x9d.
The protective effect in such a stabilized active substance is much more efficient than in the case of merely mixing or granulating starting powders of active substance and excipients of the pharmaceutical formulation, even in a wet process, as performed in EP 0 336 298 A. Moreover, since already the active substance HMG-CoA reductase inhibitor as such (in bulk) is efficiently protected against deleterious environmental factors due to the excellent homogeneous distribution with the buffering substance or the basifying substance, the active substance HMG-CoA reductase inhibitor can be handled more conveniently and stably stored as such, if desired, before being added to the pharmaceutical formulation. In particular, the homogeneous composition of the active substance according to the present invention is highly resistant to the negative effect of carbon dioxide and moisture from the air, and a much better protection against low pH conditions is achieved when the composition containing the active substance HMG-CoA reductase inhibitor is incorporated as the active substance into the final pharmaceutical formulation.
Accordingly, the present invention also makes available a newly stabilized pharmaceutical formulation comprising the aforementioned specific composition as the active substance.
According to the present invention, there is further provided a process for preparing a stabilized HMG-CoA reductase inhibitor which comprises the step of crystallization and/or precipitation of the HMG-CoA reductase inhibitor with the buffering substance or the basifying substance.